All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
When a patient is at end stage heart failure or suffers from severe coronary artery disease, the patient faces limited treatment options. The most effective treatment for these patients is heart transplantation, where the patient's diseased heart is replaced with a healthy heart from a deceased donor. The short term survival rate for patients receiving a heart transplant is high, approaching 85% of patients one year after transplantation. Despite improvements prolonging the short term survival of heart transplant recipients, the long term graft survival rate remains poor, dropping to under 50% after 10 years.
The leading cause of death after heart transplantation is allograft rejection, either chronic or acute, where the recipient's immune system attacks the transplanted organ. To combat allograft rejection, recipients of a heart transplant must take a regimen of immunosuppressant drugs for the remainder of their life. However, immunosuppressant drugs are not without their side effects. In addition to preventing allograft rejection, the administration of immunosuppressant drugs also weakens a transplant recipient's immune system. As a result, the transplant recipient has an inhibited ability to ward off common colds, infections and other illness. To mitigate the effects of immunosuppressant therapy, the dosage the transplant recipient receives is limited as much as possible. The balance between limiting the dosage of the immunosuppressant regimen and combating transplant rejection is maintained by constant monitoring of the transplant recipient to guide immunosuppressant therapy.
Currently, the standard method for monitoring rejection of a cardiac allograft is through endomyocardial biopsy. These biopsies are typically performed once a week initially, and slowly taper over time to a frequency of once every three to six months. During an endomyocardial biopsy, the patient is administered a local anesthetic, and a special type of catheter called a biotome is inserted into a vein in the patient's neck or groin. The biotome is guided into the right side of the patient's heart, where it takes approximately four tissue samples from one to four millimeters in size from the right ventricular septum. These tissue samples are analyzed under a microscope to determine the degree of rejection in the allograft, which is indicated by the infiltration of mononuclear cells in the allograft tissue, and the extent of interstitial fibrosis and myocyte degeneration.
Despite its widespread use, endomyocardial biopsy has several serious limitations. Namely, the procedure can only detect cardiac allograft rejection after cellular infiltration and/or significant graft damage have occurred. In addition, the procedure is expensive, costing approximately $1200 to $4000 per procedure, as well as invasive and uncomfortable for patients. Furthermore, such tests cannot be conducted remotely as they require office or hospital visits. Consequently, there exists a need in the art for alternative methods for detection of cardiac allograft rejection.